Monitoring and Special Considerations for Multi-Center Trials

September 10, 2010

Pav Aujla, MS, CCRP, RACPrimo N. Lara, Jr. MD

A Translational Innovation Forum

Agenda• Basic principles of:

• Investigator’s Responsibilities• Sponsor’s Responsibilities• Monitor’s Responsibilities• “Sponsor – Investigator’s” Responsibilities

• Investigator-Initiated Trials (IITs)

• Investigator-Initiated Multi-Center Trials

Agenda• Types of Monitoring Visits:

• Study Initiation Visit (SIV)• Periodic Monitoring Visits• Study Termination/Closeout (COV)

Agenda Understand safety reporting, record retention,

and FDA regulations, among other important elements

International Conference of Harmonization for Good Clinical Practice (E6)

A common approach to clinical research Represents a “passport” to global use of clinical

trial data Establishes common definitions and reporting

guidelines for adverse events

International Conference of Harmonization for Good Clinical Practice (E6)

1. Glossary2. Principles of GCP3. IEC/IRBResponsibilities4. Investigator’sResponsibilities

5. Sponsor’sResponsibilities6. Protocols andAmendments7. Investigator’sBrochure8. Essential Documents

What are GCPs?

Good Clinical Practices are the ethical, scientific andregulatory standards for conducting research

involving human subjects.

Essential Elements- Data Integrity

- Patient rights and safety

Is GCP training available at UCDHS?

Yes, there is a GCP online training program on the CITI training site

CITI homepage: http://www.citiprogram.org

ICH GCP Section 4Investigator□ 4.1 Investigator’s Qualifications and Agreements□ 4.2 Adequate Resources□ 4.3 Medical Care of Trial Subjects□ 4.4 Communication with IRB□ 4.5 Compliance with Protocol□ 4.6 Investigational Product(s)□ 4.7 Randomization Procedures and Unblinding□ 4.8 Informed Consent of Trial Subjects□ 4.9 Records and Reports□ 4.10 Progress Reports□ 4.11 Safety Reporting□ 4.12 Premature Termination or Suspension of a Trial□ 4.13 Final Report(s) by Investigator

Investigator’s Responsibilities• 4.1 Investigator’s qualifications and agreements

• Education, Training, Experience• Be familiar with protocol and IB

• 4.2 Adequate resources• Do you have the time?• Staff and facilities• Can you recruit patients under the recruitment period?

• 4.4 Medical care of subjects• Medical decisions• Adverse events

Investigator’s Responsibilities

• 4.4 Communication with IRB• 4.5 Protocol compliance• 4.6 Investigational product(s)

• Inventory, records (dates, quantities, batch/serial numbers, expiration date)

Investigator’s Responsibilities

• 4.8 Informed consent of trial subjects• 4.9 Records and reports• 4.11 Safety reporting

ICH GCP Section 5Sponsor□ 5.1 Quality Assurance and Quality Control□ 5.2 Contract Research Organization (CRO)□ 5.3 Medical Expertise□ 5.4 Trial Design□ 5.5 Trial Management, Data Handling, and Record Keeping□ 5.6 Investigator Selection□ 5.7 Allocation of Responsibilities□ 5.8 Compensation to Subjects and Investigators□ 5.9 Financing□ 5.10 Notification/Submission to Regulatory Authority(ies)□ 5.11 Confirmation of Review by IRB□ 5.12 Information on Investigational Product(s)□ 5.13 Manufacturing, Packaging, Labeling, and Coding Investigational

Product(s)

ICH GCP Section 5Sponsor□ 5.14 Supplying and Handling Investigational Product(s)□ 5.15 Record Access□ 5.16 Safety Information□ 5.17 Adverse Drug Reaction Reporting□ 5.18 Monitoring□ 5.18.1 Purpose□ 5.18.2 Selection and Qualifications of Monitors□ 5.18.3 Extent and nature of Monitoring□ 5.18.4 Monitor’s Responsibilities□ 5.18.5 Monitoring Report□ 5.19 Audit□ 5.19.1 Auditing Procedures□ 5.19.2 Selection and Qualification of Auditors□ 5.19.3 Auditing Procedures□ 5.20 Noncompliance□ 5.21 Premature Termination of a Trial□ 5.22 Clinical Trial/Study Reports□ 5.23 Multicenter Trials

Sponsor’s Responsibilities• 5.3 Medical Expertise

• Selects qualified investigators

• 5.9 Financing

• Maintains records of financial payments to investigators

• 5.10 Notification/Submission to Regulatory Authority(ies)• Maintains an effective IND with respect to the

investigations• Ensures compliance with IND

Sponsor’s Responsibilities

• 5.14 Supplying and Handling Investigational Products(s)

• Supplies the study drug in accordance to applicable regulations &

maintains necessary records of receipt, shipment & disposition of

study drug

• 5.16 Safety Information

• Ensures that FDA & investigators are informed of significant new

adverse effects

ICH GCP Section 5Monitor

□ 5.18 Monitoring□ 5.18.1 Purpose□ 5.18.2 Selection and Qualifications of

Monitors□ 5.18.3 Extent and Nature of Monitoring□ 5.18.4 Monitor’s Responsibilities□ 5.18.5 Monitoring Report

Monitor’s Responsibilities

• Ensures clinical studies are conducted and reported in compliance

with the approved protocol, SOPs, GCPs, and with applicable

country and state-specific regulatory requirement(s)

• Ensures that the rights and well being of human subjects are

protected

• Confirms reported trial data are accurate, complete, and verifiable

from source documents

Common Deficiencies (when GCPs are not followed)

• Failure to follow protocol• Inadequate informed consent process, record

keeping, drug accountability• Failure to report adverse events in a timely

manner• Inadequate monitoring• Failure to submit IND amendment/progress

reports

Investigator-Initiated Trials (IITs): “Sponsor – Investigator”

Investigator-Initiated Trials (IITs)

Investigator comes up with the concept and designs the protocol Review literature/preclinical data Calculate sample size Trial cost

Investigator gets the study “up and going”

Investigator-Initiated Trials (IITs) Highest priority studies within the Cancer Center Viewed as of higher academic value Typically, the investigator serves as both investigator and

sponsor roles Preferred UC Davis term: “Sponsor-Investigator”

Most IITs are single institution; however, some may require multi-institution involvement

Monitoring of multi-institutional IITs are more resource demanding Ensure that this is accounted for in the IIT budget!!!

Investigator-Initiated Trials (IITs)

Active to Accrual studies 10 IITs/Single Institution

4 with Pharmaceutical Industry Support2 with Lawrence Livermore National

Laboratory4 with UCDCC support only

Investigator-Initiated Multi-center Trials:

“Sponsor – Investigator”

Investigator-Initiated Multi-center Trials Single protocol conducted at more than one location Inter-Institutional Agreements Determine Authorship Policies Register trial with clinicaltrials.gov Oversee regulatory documents Adverse Events Reporting - Central Monitoring Body Site Monitoring ?? CC does not have the funds to do this

Investigator-Initiated Multi-center Trials Active to Accrual studies

5 IITs/Multi-Center4 with Pharmaceutical Industry Support1 with UCDCC support only

Types of Monitoring Visits

• Study Initiation Visit (SIV)• Periodic Monitoring Visits• Study Termination/Closeout (COV)

Study Initiation Visit (SIV) Verify that all required documents and supplies

are available at the site, and that the study team is ready to enroll patients.

Some items discussed at Site Initiation Visit: Review the study protocol

Eligibility Criteria Treatment Procedures

Periodic Monitoring Visits

Verify informed consent for each subject enrolled Assess IRB status Review study files

Check source documents Identify deviations and protocol violations

Study Closeout/Termination The following activities are performed when a trial

is completed as planned (close-out) or prematurely (termination). Final review of all study documents Inventory, itemize, return or destroy unused supplies

and/or study treatment Obtain copies of any source documents only available in

the medical records or ensure that medical records are not destroyed in the event of subject’s death

Study Closeout/Termination Ensure that the regulatory files are complete and current Provide the sponsor with a summary overview of the

study documenting official close Once all study activities are completed, submit the final

report to the IRB Prepare a quick reference file including subject

identification code list, sponsor contacts and document storage location for future reference

Maintain study records according to long-term storage requirements

Safety Reporting

• Definitions (21 CFR §314.80)• Serious Adverse Experience

• Reporting Requirements

SAE Processing for UCD Patients

Study Coordinator completes SAE Report

per protocol

Study Coordinator completes “UCDCC

Serious Adverse Event Cover Sheet”

SAE is identified by CTSU Staff

Fax MedWatch Form to FDA

“Acknowledgement of Receipt” Letter from

FDA

Study Coordinator and PI determine

event was unanticipated, related

and increase risk

UCDCC Serious Adverse Event Cover

and SAE report submitted to CC

Database

Study Coordinator submits ‘”Report of Unanticipated

Problems Involving Risk to Participants or Others” to

IRB

[SAE Report = IND Safety Report or MedWatch Form]

Safety Reporting

Document and report all adverse events

Report Serious Adverse Events to IRB per IRB SOPs

Document all information regarding adverse events in the source document

Clinical Trial Documentation

Communications with subjects Shipping records Accountability logs

Documentation of used and unused drug supply returned to the Sponsor

IRB approvals for study protocol and all amendments All source documents and laboratory records Essential regulatory documents (ie. FDA form 1572s) Any other pertinent study document

Clinical Trial Documentation

Record Retention

Clinical trial data records (GCP)At least 2 years after• The IND is discontinued (If no NDA is submitted)• 5 years after submission of an NDA• May have to keep the documents for a longer period

of time

Summary Be familiar with GCPs! Know your responsibilities as the “Sponsor-Investigator” Initiating a multi-center trial is complex Research whether the trial can be conducted at external

sites Establish excellent communication with external sites Have the resources to provide administrative and other

support to ensure proper conduct of the study

References

21 CFR 50, 54, 56, 312 Friedman et al. Fundamentals of Clinical Trials, 3rd

Edition 1999 FDA Guidance for Industry:

ICH E6 Good Clinical Practice Guideline for the Monitoring of Clinical Investigations

Helpful Links

Investigator’s Handbookhttp://ctep.cancer.gov/investigatorResources/investigators_handbook.htm• ICH websitehttp://www.ich.org• US Department of Health and Human Serviceshttp://www.youtube.com/user/USGOVHHS#g/c/

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Questions? Clarifications?